Interpretive Summary: Because of problems with the development of resistance to conventional pesticides, there is a critical need for new concepts and alternative approaches in controlling insect pests. Neuropeptides (short chains of amino acids) serve as potent messengers in insects to regulate vital functions, but hold little promise as pest control agents because they may be degraded inside pests and cannot penetrate the outside surface of pest insects. New, selective control measures may be developed by designing metabolically stable mimics of these neuropeptides that interact with the active site within the agricultural or medical pest to either inhibit or over-stimulate critical neuropeptide-regulated life functions. We report on the discovery of a unique strategy for the development of versions of neuropeptides of the pyrokinin class that can either selectively mimic or block neuropeptide actions that regulate an insect’s defense mechanisms. The work was made possible due to the development of a new chemical framework that mimics the 3-D structure of the natural neuropeptide and further enhances its biostability. The work brings us one step closer to the development of practical neuropeptide-like substances that will effectively control pest arthropods in an environmentally friendly fashion.

Technical Abstract:
ABSTRACT
In recent years, peptidomics studies have swelled the ranks of the invertebrate pyrokinin (PK) superfamily, which plays a multifunctional role in an array of important physiological processes in a variety of insects. The strong activity observed for a PK active core analog containing an (E)-alkene, transPro isosteric component in six disparate PK bioassay systems provided strong evidence for the orientation of Pro and the core conformation adopted by PK neuropeptides during interaction with disparate PK receptors. A PK active core analog incorporating a second, novel transPro conformational-mimetic motif, the dihydroimidazole moiety, was found to demonstrate pure, selective agonism in a melanotropic bioassay, with no significant activity in three other PK bioassays. A second PK core analog incorporating the dihydroimidazole moiety proved to be an antagonist of the diapause-termination activity of diapause hormone, a member of the PK superfamily of neuropeptides. Both of these dihydroimidazole analogs feature a modification adjacent to the primary tissue-bound peptidase hydrolysis site that is expected to enhance biostability over natural PK peptides. The research identifies a novel scaffold with which to design either selective-agonist or antagonist, mimetic PK analogs as potential leads in the development of environmentally favorable pest management agents capable of disrupting PK-regulated systems.